In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Abstract

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.

Response to Systemic Therapies in Ovarian Adult Granulosa Cell Tumors: A Literature Review

“…Examples of novel approaches include a master protocol [ 51 ], such as the BASKET trial performed by How et al [ 52 ], and in vitro drug screens. Haltia et al [ 53 ] previously tested many different therapies using drug screens, and Roze et al [ 54 ] recently demonstrated the use of patient-derived aGCT cell lines for drug screens. Further research could comprise a study with the design of an umbrella trial [ 51 ].…”

Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro

“…Similar to many other tumor cells [ 7 ], the only available AGCT cell line, KGN, expresses appreciable levels of caspase-3 ( Figure S2 ). We examined whether this property could be exploited to induce KGN cell killing by treating with increasing concentrations of PAC-1 up to 40 µM ( Figure 1 A).…”

“…Surgery is the primary treatment modality and both European and American clinical guidelines recommend platinum-based therapies if chemotherapy is warranted [ 4 , 5 ]. However, multiple retrospective analyses of case histories have shown that there is no survival advantage between adjuvant chemotherapy, radiotherapy, and observation [ 6 , 7 ]. There are two forms of GCT, adult (AGCT) and juvenile GCT, with 95% of GCTs being AGCT [ 2 ].…”

“…Roze et al examined responses of AGCT patient-derived cell cultures to 11 monotherapies and 12 combination therapies. None of the monotherapies tested were very effective, but their study indicates a potential for combination of carboplatin, paclitaxel, and the kinase inhibitor alpelisib for treating this disease [ 7 ].…”

JAK/STAT Signaling: Molecular Targets, Therapeutic Opportunities, and Limitations of Targeted Inhibitions in Solid Malignancies

“…However, combinatorial study has revealed the synergistic effect of dasatinib and paclitaxel on the inhibition of growth of ovarian granulosa cell tumor cells. IL-6, one of the critical cytokines that recruits gp130, forms IL-6/IL-6R/GP130 complex to activate STAT3 ( Roze et al, 2021 ). The IL-6/gp130/STAT3 signaling axis is frequently aberrant in many tumors.…”